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Mexiletine, a decades-old drug previously used to treat abnormal heart rhythms, has been used to alleviate the symptoms of patients with nondystrophic myotonias
(NDMs), rare diseases that affect the skeletal muscle and cause functionally
limiting stiffness and pain.

The preliminary research, published today in The Journal of the American Medical
Association, shows that taking mexiletine
can improve patient-reported stiffness.

NDMs are estimated to affect about 1 in every
100,000 people. They are not life-threatening, but can be debilitating, as
patients’ muscles contract and won’t relax, causing functionally limiting pain,
stiffness and fatigue which can often be severe enough to stop the patient from
being able to work.

The study was carried out in 59 patients at seven
neuromuscular referral centres in four countries, the largest number of which
were recruited through the NIHR Biomedical Research Centre at University
College London Hospitals NHS Foundation Trust and University College London.

Professor Michael Hanna at the MRC Centre for Neuromuscular
Diseases led a UCL team including MRC training fellow Dr Dipa Raja Rayan.

Professor Hanna, a senior author on the
paper, says: “These disorders can be extremely severe and the effects can stop
people from working. Patients who took the repurposed drug, mexiletine,
reported that their stiffness improved, they had less pain and they also
performed better on handgrip tests. The findings are exciting because this
treatment can make the difference between patients being able to work and not,
but further research is required.

It is harder to do clinical trials in rare diseases because individual researchers aren’t able to see the volume of patients required... (but) finding treatments for rarer diseases is an important goal for the NIHR University College London Hospitals Biomedical Research Centre.

Professor Michael Hanna, MRC Centre for Neuromuscular Diseases at UCL

“It is harder to do clinical trials in rare diseases such as
nondystrophic myotonias because individual researchers aren’t able to see the
volume of patients required. However, if you are a patient with a rarer disease
– something which is harder to study – you should still have access to research
and treatment. That’s why we set up this international collaboration to pool
our resources and share information. Finding treatments for rarer diseases is
an important goal for the NIHR University College London Hospitals Biomedical
Research Centre.”

Data on
treatment of NDMs are largely anecdotal, consisting of case series and
single-blind, controlled trials of several medications including mexiletine,
according to background information in the article.

This new international study was conducted to determine the effects of mexiletine for
symptoms and signs of myotonia (prolonged failure of muscle relaxation after
contraction) in patients with NDMs. The randomized study, part of the National
Institutes of Health-funded Rare Disease Clinical Research Network, was
carried out between
December 2008 and March 2011 and included 59 patients with NDMs.

The patients (33
men, 26 women; average age, 43 years) received either oral 200-mg mexiletine or
placebo capsules three times daily for four weeks, followed by the opposite
intervention for four weeks, with 1-week washout in between.

The main outcome
measured for the study was a patient-reported severity score of stiffness,
recorded on an interactive voice response (IVR) diary. Secondary outcomes included IVR-reported changes
in pain, weakness, and tiredness; clinical myotonia assessment; quantitative
measure of handgrip myotonia; and an Individualized Neuromuscular Quality of Life
summary score.

Data from
57 participants who made telephone calls to the IVR diary were included in the analysis and the researchers found that
mexiletine was associated with significantly improved levels of stiffness as reported.

There were
significant improvements with mexiletine in most other outcomes in the study,
including patient-reported outcomes, quality of life scales, and quantitative
measures of myotonia (improved myotonia as measured on clinical examination by
overall handgrip times in seconds).

“The most
common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two
participants experienced transient cardiac effects that did not require
stopping the study (1 in each group). One serious adverse event was determined
to be not study related,” the authors write in the paper.

“Our study
provides preliminary evidence of the effectiveness of mexiletine for symptoms
and signs of myotonia in NDMs,” the researchers continue. “The clinical
significance of the improvement in stiffness score on the IVR diary is
supported by the broad improvement in clinical, quantitative, and
electrophysiological measures of myotonia.”